Transdermal delivery of high viscosity bioactive agents

ABSTRACT

A device and method for delivering a high viscosity composition is described. The composition includes a bioactive agent for delivery to a subject in need thereof. The method delivers the bioactive agent at a high bioavailability and with little loss of agent to the natural defense mechanisms of the body. The device includes one or more microneedles with structures fabricated on a surface of the microneedles to form a nanotopography. A random or non-random pattern of structures may be fabricated such as a complex pattern including structures of differing sizes and/or shapes.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation application of U.S. patentapplication Ser. No. 15/411,318, filed on Jan. 20, 2017, the entirecontents of which are incorporated herein by reference. U.S. patentapplication Ser. No. 15/411,318 is a continuation application of U.S.patent application Ser. No. 14/354,229, filed on Apr. 25, 2014, which isnow U.S. Pat. No. 9,550,053, the entire contents of which areincorporated herein by reference. U.S. patent application Ser. No.14/354,229 is the U.S. national stage application of InternationalApplication No. PCT/IB2012/055621, filed on Oct. 16, 2012, the entirecontents of which are incorporated herein by reference. InternationalApplication No. PCT/IB2012/055621 claims priority to U.S. ProvisionalPatent Application No. 61/552,069, filed on Oct. 27, 2011, the entirecontents of which are incorporated herein by reference.

BACKGROUND

Targeted drug delivery in which a bioactive agent (e.g., a drug or atherapeutic) is provided in an active state to a subject's system ateffective concentrations is a long sought goal. Many difficulties mustbe overcome to reach this goal. For instance, a bioactive agent mustfirst be successfully delivered internally, and the human body hasdeveloped many barriers to prevent the influx of foreign substances. Inaddition, the nature of the bioactive agent itself or the concentrationof a bioactive agent necessary to obtain the desired effect often leadsto formation of a high viscosity composition, which further amplifiesthe difficulties in successfully passing the body's natural barriers.

Delivery methods presently utilized for high viscosity compositionsinclude oral delivery, injections, and infusions. Unfortunately, thesemethods all include aspects that are problematic not only with regard tosuccessful delivery of the high viscosity composition, but also for thesubject receiving the composition. For instance, injections oftenutilize small gauge needles that require extremely high pressure over along period of time for delivery of high viscosity compositions, if theyare capable of use for the high viscosity compositions at all. Forexample, 0.5 milliliter of a 20 centipoise (cP) proteinaceous solutioncan take up to about 600 seconds for delivery through a 34 gauge needle.In addition, injections are painful particularly when considering thetime required for a single dose delivery and, when considering long termuse of an agent, can lead to development of scar tissue. Oral deliveryrequires successful absorption through the epithelial lining of thedigestive tract as well as avoidance of break down of the bioactiveagent by digestive materials, and both of these hurdles can be extremelydifficult to cross. In addition, oral delivery often leads togastrointestinal distress for the subject. Moreover, both injection andoral delivery tend to provide bursts of agents and wide swings in systemconcentration rather than a preferred steady-state delivery. Infusiontherapy can be used to deliver bioactive agents directly to bloodvessels, muscles, or subcutaneous connective tissue. While delivery viainfusion therapy now can be carried out on an out-patient basis, or evenwith long term, relatively steady-state delivery by use of infusionpumps, infusion therapy is invasive, increasing chances for infection atthe infusion site, and necessitates the utilization of associatedequipment such as pumps, transdermal tubing, etc.

Transdermal delivery devices have been developed in an attempt toprovide a painless route for successful delivery of bioactive agentsover a sustained period. For instance, transdermal delivery patches havebeen found useful for providing bioactive agents such as nicotine,scopolamine, estrogen, nitroglycerine, and the like to a subject'ssystem. In order to be successful, a transdermal scheme must deliver anagent across the epidermis, which has evolved with a primary function ofkeeping foreign substances out. The outermost layer of the epidermis,the stratum corneum, has structural stability provided by overlappingcorneocytes and crosslinked keratin fibers held together bycoreodesmosomes and embedded within a lipid matrix, all of whichprovides an excellent barrier function. Beneath the stratum corneum isthe stratum granulosum, within which tight junctions are formed betweenkeratinocytes. Tight junctions are barrier structures that include anetwork of transmembrane proteins embedded in adjacent plasma membranes(e.g., claudins, occludin, and junctional adhesion molecules) as well asmultiple plaque proteins (e.g., ZO-1, ZO-2, ZO-3, cingulin, symplekin).Tight junctions are found in internal epithelium and endothelium (e.g.,the intestinal epithelium, the blood-brain barrier, blood vessel walls)as well as in the stratum granulosum of the skin. Beneath both thestratum corneum and the stratum granulosum lays the stratum spinosum.The stratum spinosum includes Langerhans cells, which are dendriticcells that may become fully functioning antigen-presenting cells and mayinstitute an immune response and/or a foreign body response to aninvading agent.

The addition of microneedles on transdermal delivery devices such aspatches has helped to breach initial barriers in the dermis.Unfortunately, even with such improvements, transdermal delivery devicesare presently limited to delivery of low viscosity compositions, and inparticular low molecular weight agents that have a moderatelipophilicity and no charge. Moreover, even upon successful crossing ofthe natural boundary, problems still exist with regard to maintainingthe activity level of delivered agents and avoidance of foreign body andimmune response.

What are needed in the art are devices and methods for delivery ofbioactive agents. More specifically, what are needed are devices andmethods that can successfully deliver a high viscosity composition thatincludes a bioactive agent and can also prevent targeting of thebioactive agent by the body's own defensive mechanisms.

SUMMARY

According to one embodiment, disclosed is a device for delivery of acomposition across a dermal barrier. More specifically, the device mayinclude a microneedle and a plurality of nanostructures fabricated on asurface thereof. The nanostructures can be arranged in a predeterminedpattern. The device also includes the composition in fluid communicationwith the microneedle. More specifically, the composition includes abioactive agent and can have a viscosity of greater than about 5centipoise.

According to another embodiment, disclosed is a method for delivering acomposition to a subject. The method includes penetrating the stratumcorneum of the subject with a microneedle that is in fluid communicationwith the composition. The composition includes a bioactive agent and hasa viscosity greater than about 5 centipoise. In addition, themicroneedle includes a plurality of nanostructures formed on a surfacethereof in a pattern. The method also includes transporting thebioactive agent through the microneedle at a rate of greater than about0.4 mg/hr/cm² based upon the surface area of the microneedle.

BRIEF DESCRIPTION OF THE DRAWINGS

A full and enabling disclosure of the subject matter, including the bestmode thereof, directed to one of ordinary skill in the art, is set forthmore particularly in the remainder of the specification, which makesreference to the appended figures in which:

FIG. 1 illustrates one embodiment of a microneedle device.

FIG. 2 illustrates another embodiment of a microneedle device.

FIG. 3 illustrates one embodiment of a microneedle including a surfacethat defines a nanotopography that may interact with an extracellularmatrix (ECM).

FIG. 4 illustrates one embodiment of a complex pattern that may beformed on a microneedle surface.

FIG. 5 illustrates a pattern including multiple iterations of thecomplex pattern of FIG. 4.

FIG. 6 illustrates a Sierpinski triangle fractal.

FIGS. 7A-7D illustrate complex fractal and fractal-likenanotopographies.

FIG. 8 illustrates another complex pattern that may be formed on amicroneedle surface.

FIG. 9 illustrates exemplary packing densities as may be utilized fornano-sized structures as described herein including a square packingdesign (FIG. 9A), a hexagonal packing design (FIG. 9B), and a circlepacking design (FIG. 9C).

FIGS. 10A-10C schematically illustrate a nanoimprinting method as may beutilized in one embodiment in forming a device.

FIG. 11 schematically illustrates one embodiment of a device including arelease liner (FIG. 11A) and following removal of the release liner(FIG. 11B).

FIG. 12 is a perspective view of one embodiment of a transdermal patchprior to delivery of a drug compound.

FIG. 13 is a front view of the patch of FIG. 12.

FIG. 14 is a perspective view of the patch of FIG. 12 in which therelease member is partially withdrawn from the patch.

FIG. 15 is a front view of the patch of FIG. 14.

FIG. 16 is a perspective view of the transdermal patch of FIG. 12 afterremoval of the release member and during use.

FIG. 17 is a front view of the patch of FIG. 16.

FIG. 18 is a perspective view of another embodiment of a transdermalpatch prior to delivery of a drug compound.

FIG. 19 is a front view of the patch of FIG. 18.

FIG. 20 is a perspective view of the patch of FIG. 18 in which therelease member is partially peeled away from the patch.

FIG. 21 is a front view of the patch of FIG. 20.

FIG. 22 is a perspective view of the patch of FIG. 18 in which therelease member is completely peeled away from the patch.

FIG. 23 is a perspective view of the transdermal patch of FIG. 18 afterremoval of the release member and during use.

FIGS. 24A-24E illustrate several nanotopography patterns as describedherein.

FIG. 25 is an SEM of a film including a nanopatterned surface.

FIGS. 26A and 26B are two SEM of a film including another nanopatternedsurface.

FIG. 27 is an SEM of a film including another nanopatterned surface.

FIG. 28 is an SEM of a film including another nanopatterned surface.

FIG. 29 is an SEM of a film including another nanopatterned surface.

FIG. 30 is an SEM of a film including another nanopatterned surface.

FIG. 31 is an SEM of a film including another nanopatterned surface.

FIG. 32 is an SEM of a film including another nanopatterned surface.

FIG. 33 is an SEM of a film including another nanopatterned surface.

FIGS. 34A-34D are images of a microneedle array as described herein atincreasing magnification.

DETAILED DESCRIPTION OF REPRESENTATIVE EMBODIMENTS

Reference now will be made in detail to various embodiments of thedisclosed subject matter, one or more examples of which are set forthbelow. Each example is provided by way of explanation, not limitation.In fact, it will be apparent to those skilled in the art that variousmodifications and variations may be made in the present disclosurewithout departing from the scope or spirit of the subject matter. Forinstance, features illustrated or described as part of one embodimentmay be used on another embodiment to yield a still further embodiment.Thus, it is intended that the present disclosure covers suchmodifications and variations as come within the scope of the appendedclaims and their equivalents.

Devices and methods are described herein that provide a route fordelivering a composition including a bioactive agent across a dermalbarrier of a subject, the transdermal delivery device including one ormore microneedles. More specifically, the composition can have a highviscosity, and in particular a viscosity that in the past has not beenconsidered deliverable by use of transdermal devices, e.g., a viscositygreater than about 5 centipoise. Methods can include delivery of thehigh viscosity bioactive agent to the subject at a useful rate, forinstance at a rate of greater than about 5 mg/mL per hour. The highviscosity of the composition can be due to, for example, a highconcentration of the bioactive agent in the composition, a highmolecular weight bioactive agent in the composition, high molecularweight or high concentration adjuvants in the composition, or acombination of factors. For instance, the composition can include one ormore high molecular weight bioactive agents, such as proteintherapeutics having a molecular weight greater than about 100 kDa. Inthe past, it has proven difficult or impossible to obtain transdermaldelivery of such bioactive agents due to an inability to breach thebody's natural barriers.

Subjects as may benefit from the methods can include any animal subjectin need of delivery of a bioactive agent. For instance a subject can bea human or any other mammal or animal as may benefit from the deliverymethods.

The delivery method utilizes a transdermal delivery device that includesone or more microneedles and a pattern of structures fabricated on asurface of at least one of the microneedles. In addition, at least aportion of the structures fabricated on a surface of the microneedle arefabricated on a nanometer scale. As utilized herein, the term‘fabricated’ generally refers to a structure that has been specificallydesigned, engineered, and/or constructed so as to exist at a surface ofa microneedle and is not to be equated with a surface feature that ismerely an incidental product of the formation process. Thus, thetransdermal delivery device will include a predetermined pattern ofnanostructures, i.e., a nanotopography, on the surface of a microneedle.

Without wishing to be bound by any particular theory, it is believedthat through interaction between the nanotopography on a surface of themicroneedle and surrounding biological materials or structures, themicroneedle may regulate and/or modulate membrane potential, membraneproteins, and/or intercellular junctions (e.g., tight junctions, gapjunctions, and/or desmasomes) of and between cells in the areasurrounding the microneedle. More specifically, it is believed thatinteraction between the nanotopography of the microneedle and thesurrounding biological materials can rearrange epithelial tightjunctions of the dermal tissue and temporarily increase porosity of thelocal barrier structures. This can encourage transport of the highviscosity composition carrying the bioactive agent across not only thedermal barrier.

In addition, it is believed that interaction between the nanotopographyof the device and the surrounding biological structures can encouragetransport of the composition carrying the bioactive agent across othernatural barriers to systemic delivery, beyond the dermal barriers.Specifically, through utilization of the nanostructured transdermaldelivery devices, the permeability is increased not only in tissue inthe immediate, contacting area of the device, but also in surroundingtissue. It is believed that increased permeability can occur not onlybetween cells in contact with the microneedle, but this effect can beperturbed to other cells in the area, including cells of differenttissue types. This can translate the increased porosity effect to nearbystructures and tissue types, which can increase porosity of nearbyvasculature.

The interaction between the device and the contacting tissue isunderstood to lead to the rearrangement of epithelial tight junctions ofthe dermal tissue, and this instigates a cascade response that transfersa similar effect to the cells of the local blood vessels, for instancecells of both the basement membrane and the endothelium of a localcapillary. This can lead to fenestration of the capillary wall, allowingentry of a bioactive agent directly to the cardiovascular system. Thiscan significantly increase uptake of the bioactive agent by thesubject's system.

By use of the devices, delivery of a high viscosity compositionincluding one or more bioactive agents can be improved. A high viscositycomposition can have a viscosity of, for example, greater than about 5centipoise, greater than about 10 centipoise, or greater than about 25centipoise. In one embodiment, the composition can have a viscosity offrom about 10 centipoise to about 50 centipoise, for instance, fromabout 30 centipoise to about 40 centipoise.

Viscosity of a composition can be determined according to standardpractice. For instance, one approach to measuring viscosity calls forinserting a piston into a closed vessel containing the sample fluid, andthen measuring the torque required to rotate the piston in the vessel.While this approach is adequate for measuring the viscosity of largerfluid samples, it offers the disadvantage of requiring and consumingrelatively large volumes of sample fluid. Such volumes may not beavailable for analysis, particularly in the context of biologicalanalysis.

In accordance with an alternative method, diffusion of a marker of knownsize and diffusion coefficient (i.e. a fluorescently labeled bead ormacromolecule) across a microfluidic free interface created within thecomposition may be utilized to determine the viscosity. Such a techniqueis applicable to analysis of the viscosity of biological orphysiological samples, as the dimensions of the microfluidic channels inwhich diffusion occurs occupies relatively small volumes.

Viscosity of a composition can be determined through use of standardmeters, for instance a capillary viscometer as is known in the art.Exemplary rheometers as may be utilized include, without limitation, theBrookfield™ programmable rheometer, LV-DV-III, an Ostwald viscositymeter, a VROC® viscometer rheometer-on-a-chip, which is a micron scaleviscosity sensor chip for small samples, a Haake Viscotester™ VT 550rheometer, and the like.

The devices can deliver a high viscosity composition at a useful rate toa subject in need thereof. For instance, a high viscosity compositioncan be transdermally delivered at a rate of greater than about 0.4mg/hr/cm², greater than about 1 mg/hr/cm², greater than about 3mg/hr/cm², or greater than about 6 mg/hr/cm², based upon the surfacearea of the microneedle.

There is no particular limitation to bioactive agents as may bedelivered by use of the methods. Bioactive agents can encompass naturalor synthetic agents, small molecule agents, and so forth. In oneembodiment, methods may be utilized for delivery of high molecularweight bioactive agents (e.g., non-proteinaceous synthetic or naturalbioactive agents defining a molecular weight greater than about 400 Da,greater than about 10 kDa, greater than about 20 kDa, or greater thanabout 100 kDa, e.g., about 150 kDa).

In one particular example, a bioactive agent delivered according to themethods can be a high molecular weight protein therapeutic. As utilizedherein, the term ‘protein therapeutics’ generally refers to anybiologically active proteinaceous compound including, withoutlimitation, natural, synthetic, and recombinant compounds, fusionproteins, chimeras, and so forth, as well as compounds including the 20standard amino acids and/or synthetic amino acids. By way of example, aprotein therapeutic having a molecular weight of greater than about 100kDa, or greater than about 125 kDa, for instance from about 125 kDa toabout 200 kDa, or from about 150 kDa to about 200 kDa, can be deliveredtransdermally via the methods.

In one embodiment, the methods and devices may be utilized for deliveryof a composition including a high concentration of a bioactive agent,either a large molecular weight bioactive agent or a small moleculebioactive agent. By way of example, a composition can include abioactive agent in a concentration of greater than about 5 mg/mL,greater than about 10 mg/mL, greater than about 30 mg/mL, greater thanabout 50 mg/mL, greater than about 100 mg/mL, or greater than about 200mg/mL. For instance, the composition can include a bioactive agent in aconcentration of from about 35 mg/mL to about 500 mg/mL or from about 50mg/mL to about 400 mg/mL.

Agents may include proteinaceous agents such as insulin, immunoglobulins(e.g., IgG, IgM, IgA, IgE), TNF-α, antiviral medications, and so forth;polynucleotide agents including plasmids, siRNA, RNAi, nucleosideanticancer drugs, vaccines, and so forth; and small molecule agents suchas alkaloids, glycosides, phenols, and so forth. Agents may includeanti-infection agents, hormones, drugs that regulate cardiac action orblood flow, pain control, and so forth. Still other substances which maybe delivered in accordance with the present disclosure are agents usefulin the prevention, diagnosis, alleviation, treatment, or cure ofdisease. A non-limiting listing of agents includes anti-Angiogenesisagents, anti-depressants, antidiabetic agents, antihistamines,anti-inflammatory agents, butorphanol, calcitonin and analogs, COX-IIinhibitors, dermatological agents, dopamine agonists and antagonists,enkephalins and other opioid peptides, epidermal growth factors,erythropoietin and analogs, follicle stimulating hormone, glucagon,growth hormone and analogs (including growth hormone releasing hormone),growth hormone antagonists, heparin, hirudin and hirudin analogs such ashirulog, IgE suppressors and other protein inhibitors,immunosuppressives, insulin, insulinotropin and analogs, interferons,interleukins, leutenizing hormone, leutenizing hormone releasing hormoneand analogs, monoclonal or polyclonal antibodies, motion sicknesspreparations, muscle relaxants, narcotic analgesics, nicotine,non-steroid anti-inflammatory agents, oligosaccharides, parathyroidhormone and analogs, parathyroid hormone antagonists, prostaglandinantagonists, prostaglandins, scopolamine, sedatives, serotonin agonistsand antagonists, sexual hypofunction, tissue plasminogen activators,tranquilizers, vaccines with or without carriers/adjuvants,vasodilators, major diagnostics such as tuberculin and otherhypersensitivity agents as described in U.S. Pat. No. 6,569,143 entitled“Method of Intradermally Injecting Substances”, the entire content ofwhich is incorporated herein by reference. Vaccine formulations mayinclude an antigen or antigenic composition capable of eliciting animmune response against a human pathogen or from other viral pathogens.

In one embodiment, methods may be utilized in treatment of a chroniccondition, such as rheumatoid arthritis, to deliver a steady flow of anagent, to a subject in need thereof. RA drugs that can be delivered caninclude symptom suppression compounds, such as analgesics andanti-inflammatory drugs including both steroidal and non-steroidalanti-inflammatory drugs (NSAID), as well as disease-modifyingantirheumatic drugs (DMARDs).

RA drugs can include, without limitation, one or more analgesics,anti-inflammatories, DMARDs, herbal-based drugs, and combinationsthereof. Specific compounds can, of course, fall under one or more ofthe general categories described herein. For instance, many compoundsfunction as both an analgesic and an anti-inflammatory; herbal-baseddrugs can likewise function as a DMARD as well as an anti-inflammatory.Moreover, multiple compounds that can fall under a single category canbe delivered. For instance, methods can be utilized to deliver multipleanalgesics, such as acetaminophen with codeine, acetaminophen withhydrocodone (vicodin), and so forth.

A composition may include one or more bioactive agents in conjunctionwith other components as are generally known in the art. For instance, acomposition can include one or more pharmaceutically acceptableexcipients. As utilized herein, the term “excipient” generally refers toany substance, not itself a bioactive agent, used in conjunction withthe bioactive agent(s) delivered to a subject to improve one of morecharacteristics, such as its handling or storage properties or to permitor facilitate formation of a dose unit of the composition. Excipientsinclude, by way of illustration and not limitation, solvents (e.g.,lower alcohol, such as ethanol or isopropanol; or water), penetrationenhancers, thickening agents, wetting agents, lubricants, emollients,substances added to mask or counteract a disagreeable odor or flavor,fragrances, adjuvants, and substances added to improve appearance ortexture of the composition or delivery device. Any such excipients canbe used in any amounts as are generally known.

Non-limiting examples of penetration enhancing agents include C₈-C₂₂fatty acids such as isostearic acid, octanoic acid, and oleic acid;C₈-C₂₂ fatty alcohols such as oleyl alcohol and lauryl alcohol; loweralkyl esters of C₈-C₂₂ fatty acids such as ethyl oleate, isopropylmyristate, butyl stearate, and methyl laurate; di(lower)alkyl esters ofC₆-C₂₂ diacids such as diisopropyl adipate; monoglycerides of C₈-C₂₂fatty acids such as glyceryl monolaurate; tetrahydrofurfuryl alcoholpolyethylene glycol ether; polyethylene glycol, propylene glycol;2-(2-ethoxyethoxy)ethanol; diethylene glycol monomethyl ether; alkylarylethers of polyethylene oxide; polyethylene oxide monomethyl ethers;polyethylene oxide dimethyl ethers; dimethyl sulfoxide; glycerol; ethylacetate; acetoacetic ester; N-alkylpyrrolidone; and terpenes. Additionalpenetration enhancers suitable for use can also be found in U.S.Published Patent Application No. 2002/0111377, which is incorporatedherein by reference. One or more penetration enhancers, when present,can generally be present in a total amount of from about 0.01% to about25%, or from about 0.1° A to about 15% by weight of the composition.

Thickening agents (also referred to herein as gelling agents) mayinclude anionic polymers such as polyacrylic acid (Carbopol® by Noveon,Inc., Cleveland, Ohio), carboxypolymethylene, carboxymethylcellulose andthe like, including derivatives of Carbopol® polymers, such as Carbopol®Ultrez 10, Carbopol® 940, Carbopol® 941, Carbopol® 954, Carbopol® 980,Carbopol® 981, Carbopol® ETD 2001, Carbopol® EZ-2 and Carbopol® EZ-3,and other polymers such as Pemulen® polymeric emulsifiers, and Noveon®polycarbophils. Thickening agents, when present, can generally bepresent in a total amount by weight of from about 0.1 to about 15%, fromabout 0.25% to about 10%, or from about 0.5% to about 5%.

Additional thickening agents, enhancers and adjuvants may generally befound in Remington's The Science and Practice of Pharmacy as well as theHandbook f Pharmaceutical Excipients, Arthur H. Kibbe ed. 2000.

One or more neutralizing agents can be present to assist in forming agel. Suitable neutralizing agents include sodium hydroxide (e.g., as anaqueous mixture), potassium hydroxide (e.g., as an aqueous mixture),ammonium hydroxide (e.g., as an aqueous mixture), triethanolamine,tromethamine (2-amino 2-hydroxymethyl-1,3 propanediol), aminomethylpropanol (AMP), tetrahydroxypropyl ethylene diamine, diisopropanolamine,Ethomeen C-25 (Armac Industrial Division), Di-2 (ethylhexyl) amine(BASF-Wyandotte Corp., Intermediate Chemicals Division), triamylamine,Jeffamine D-1000 (Jefferson Chemical Co.), b-Dimethylaminopropionitrite(American Cyanamid Co.), Armeen CD (Armac Industrial Division), Alamine7D (Henkel Corporation), dodecylamine and morpholine. The neutralizingagent can be present in an amount sufficient to form a gel which issuitable for contact with the skin of a mammal, e.g., up to about 10% byweight of the composition, for example between about 0.1% and about 5%by weight of the composition.

A composition may include one or more pharmaceutically acceptablewetting agents (also referred to as surfactants) as excipients.Non-limiting examples of surfactants can include quaternary ammoniumcompounds, for example benzalkonium chloride, benzethonium chloride andcetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylenealkylphenyl ethers, for example nonoxynol 9, nonoxynol 10, and octoxynol9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers),polyoxyethylene fatty acid glycerides and oils, for examplepolyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g.,Labrasol™ of Gattefosse), polyoxyethylene (35) castor oil andpolyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkylethers, for example polyoxyethylene (20) cetostearyl ether,polyoxyethylene fatty acid esters, for example polyoxyethylene (40)stearate, polyoxyethylene sorbitan esters, for example polysorbate 20and polysorbate 80 (e.g., Tween™ 80 of ICI), propylene glycol fatty acidesters, for example propylene glycol laurate (e.g., Lauroglycol™ ofGattefosse), sodium lauryl sulfate, fatty acids and salts thereof, forexample oleic acid, sodium oleate and triethanolamine oleate, glycerylfatty acid esters, for example glyceryl monostearate, sorbitan esters,for example sorbitan monolaurate, sorbitan monooleate, sorbitanmonopalmitate and sorbitan monostearate, tyloxapol, and mixturesthereof. One or more wetting agents, when present, generally constitutein total from about 0.25% to about 15%, from about 0.4% to about 10%, orfrom about 0.5% to about 5%, of the total weight of the composition.

A composition may include one or more pharmaceutically acceptablelubricants (including anti-adherents and/or glidants) as excipients.Suitable lubricants include, without limitation, glyceryl behapate(e.g., Compritol™ 888); stearic acid and salts thereof, includingmagnesium (magnesium stearate), calcium and sodium stearates;hydrogenated vegetable oils (e.g., Sterotex™); colloidal silica; talc;waxes; boric acid; sodium benzoate; sodium acetate; sodium fumarate;sodium chloride; DL-leucine; PEG (e.g., Carbowax™ 4000 and Carbowax™6000); sodium oleate; sodium lauryl sulfate; and magnesium laurylsulfate. Such lubricants, when, can generally constitute from about 0.1°A to about 10%, from about 0.2% to about 8%, or from about 0.25% toabout 5%, of the total weight of the composition.

A composition may include one or more emollients. Illustrativeemollients include, without limitation, mineral oil, mixtures of mineraloil and lanolin alcohols, cetyl alcohol, cetostearyl alcohol,petrolatum, petrolatum and lanolin alcohols, cetyl esters wax,cholesterol, glycerin, glyceryl monostearate, isopropyl myristate,isopropyl palmitate, lecithin, allyl caproate, althea officinalisextract, arachidyl alcohol, argobase EUC, Butylene glycoldicaprylate/dicaprate, acacia, allantoin, carrageenan, cetyldimethicone, cyclomethicone, diethyl succinate, dihydroabietyl behenate,dioctyl adipate, ethyl laurate, ethyl palm itate, ethyl stearate,isoamyl laurate, octanoate, PEG-75 lanolin, sorbitan laurate, walnutoil, wheat germ oil super refined almond, super refined sesame, superrefined soybean, octyl palmitate, caprylic/capric triglyceride andglyceryl cocoate. A composition may include one or more emollients in atotal amount of from about 1% to about 30%, from about 3% to about 25%,or from about 5% to about 15%, by weight of the composition.

A composition may include one or more antimicrobial preservative.Illustrative anti-microbial preservatives include, without limitation,benzoic acid, phenolic acid, sorbic acids, alcohols, benzethoniumchloride, bronopol, butylparaben, cetrimide, chlorhexidine,chlorobutanol, chlorocresol, cresol, ethylparaben, imidurea,methylparaben, phenol, phenoxyethanol, phenylethyl alcohol,phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate,potassium sorbate, propylparaben, sodium propionate, or thimerosal. Oneor more anti-microbial preservatives, when present, can generally bepresent in a total amount of from about 0.1% to about 5%, from about0.2% to about 3%, or from about 0.3% to about 2%, by weight of thecomposition.

A composition may include one or more emulsifying agents. As utilizedherein, the term “emulsifying agent” generally refers to an agentcapable of lowering surface tension between a non-polar and polar phaseand includes compounds defined as “self-emulsifying” agents. Suitableemulsifying agents can come from any class of pharmaceuticallyacceptable emulsifying agents including carbohydrates, proteins, highmolecular weight alcohols, wetting agents, waxes and finely dividedsolids. One or more emulsifying agents, when present, can be present ina composition in a total amount of from about 1% to about 15%, fromabout 1% to about 12%, from about 1% to about 10%, or from about 1% toabout 5% by weight of the composition.

The composition can be prepared by any technique known to a person ofordinary skill in the art of pharmacy, pharmaceutics, drug delivery,pharmacokinetics, medicine or other related discipline that comprisesadmixing one or more excipients with a therapeutic agent to form acomposition, drug delivery system or component thereof.

A transdermal delivery device may be constructed from a variety ofmaterials, including metals, ceramics, semiconductors, organics,polymers, etc., as well as composites thereof. By way of example,pharmaceutical grade stainless steel, titanium, nickel, iron, gold, tin,chromium, copper, alloys of these or other metals, silicon, silicondioxide, and polymers may be utilized. Typically, the device is formedof a biocompatible material that is capable of carrying a pattern ofstructures as described herein on a surface. The term “biocompatible”generally refers to a material that does not substantially adverselyaffect the cells or tissues in the area where the device is to bedelivered. It is also intended that the material does not cause anysubstantially medically undesirable effect in any other areas of theliving subject. Biocompatible materials may be synthetic or natural.Some examples of suitable biocompatible materials, which are alsobiodegradable, include polymers of hydroxy acids such as lactic acid andglycolic acid polylactide, polyglycolide, polylactide-co-glycolide,copolymers with polyethylene glycol, polyanhydrides, poly(ortho)esters,polyurethanes, poly(butyric acid), poly(valeric acid), andpoly(lactide-co-caprolactone). Other suitable materials may include,without limitation, polycarbonate, polymethacrylic acid, ethylenevinylacetate, polytetrafluorethylene, and polyesters. The device may likewisebe non-porous or porous in nature, may be homogeneous or heterogeneousacross the device with regard to materials, geometry, solidity, and soforth, and may have a rigid fixed or a semi-fixed shape.

FIG. 1 illustrates a typical microneedle transdermal delivery device 10.As may be seen, the device includes an array of individual needles 12;each formed to a size and shape so as to penetrate a biological barrierwithout breakage of the individual microneedles. Microneedles may besolid, as in FIG. 1, porous, or may include a hollow portion. Amicroneedle may include a hollow portion, e.g., an annular bore that mayextend throughout all or a portion of the needle, extending parallel tothe direction of the needle or branching or exiting at a side of theneedle, as appropriate. For example, FIG. 2 illustrates an array ofmicroneedles 14 each including a channel 16 in a side of the needles asmay be utilized for, e.g., delivery of an agent to a subdermal location.For instance, a channel 16 may be in at least partial alignment with anaperture in base 15 so as to form a junction between the aperture andchannel 16 allowing the passage of a substance through the channel 16.

The dimensions of the channel 16, when present, can be specificallyselected to induce capillary flow of a composition including a bioactiveagent. Capillary flow generally occurs when the adhesive forces of afluid to the walls of a channel are greater than the cohesive forcesbetween the liquid molecules. Specifically, capillary pressure isinversely proportional to the cross-sectional dimension of the channel16 and directly proportional to the surface tension of the liquid,multiplied by the cosine of the contact angle of the fluid in contactwith the material forming the channel. Thus, to facilitate capillaryflow in the patch, the cross-sectional dimension (e.g., width, diameter,etc.) of the channel 16 may be selectively controlled, with smallerdimensions generally resulting in higher capillary pressure. Forexample, in some embodiments, the cross-sectional dimension of thechannel typically ranges from about 1 micrometer to about 100micrometers, in some embodiments from about 5 micrometers to about 50micrometers, and in some embodiments, from about 10 micrometers to about30 micrometers. The dimension may be constant or it may vary as afunction of the length of the channel 16. The length of the channel mayalso vary to accommodate different volumes, flow rates, and dwell timesfor the drug compound. For example, the length of the channel may befrom about 10 micrometers to about 800 micrometers, in some embodimentsfrom about 50 micrometers to about 500 micrometers, and in someembodiments, from about 100 micrometers to about 300 micrometers. Thecross-sectional area of the channel may also vary. For example, thecross-sectional area may be from about 50 square micrometers to about1,000 square micrometers, in some embodiments from about 100 squaremicrometers to about 500 square micrometers, and in some embodiments,from about 150 square micrometers to about 350 square micrometers.Further, the aspect ratio (length/cross-sectional dimension) of thechannel may range from about 1 to about 50, in some embodiments fromabout 5 to about 40, and in some embodiments from about 10 to about 20.In cases where the cross-sectional dimension (e.g., width, diameter,etc.) and/or length vary as a function of length, the aspect ratio canbe determined from the average dimensions.

It should be understood that the number of microneedles shown in thefigures is for illustrative purposes only. The actual number ofmicroneedles used in a microneedle assembly may, for example, range fromabout 500 to about 10,000, in some embodiments from about 2,000 to about8,000, and in some embodiments, from about 4,000 to about 6,000.

An individual microneedle may have a straight or a tapered shaft. In oneembodiment, the diameter of a microneedle may be greatest at the baseend of the microneedle and taper to a point at the end distal the base.A microneedle may also be fabricated to have a shaft that includes botha straight (untapered) portion and a tapered portion.

A microneedle may be formed with a shaft that is circular ornon-circular in cross-section. For example, the cross-section of amicroneedle may be polygonal (e.g. star-shaped, square, triangular),oblong, or any other shape. The shaft may have one or more bores and/orchannels.

The size of individual needles may be optimized depending upon thedesired targeting depth, the strength requirements of the needle toavoid breakage in a particular tissue type, etc. For instance, thecross-sectional dimension of a transdermal microneedle may be betweenabout 10 nanometers (nm) and 1 millimeter (mm), or between about 1micrometer (μm) and about 200 micrometers, or between about 10micrometers and about 100 micrometers. The outer diameter may be betweenabout 10 micrometers and about 100 micrometers and the inner diameter ofa hollow needle may be between about 3 micrometers and about 80micrometers. The tip typically has a radius that is less than or equalto about 1 micrometer.

The length of a microneedle will generally depend upon the desiredapplication. For instance, a microneedle may be from about 1 micrometerto about 1 millimeter in length, for instance about 500 micrometers orless, or from about 10 micrometers to about 500 micrometers, or fromabout 30 micrometers to about 200 micrometers.

An array of microneedles need not include microneedles that are allidentical to one another. An array may include a mixture of microneedleshaving various lengths, outer diameters, inner diameters,cross-sectional shapes, nanostructured surfaces, and/or spacings betweenthe microneedles. For example, the microneedles may be spaced apart in auniform manner, such as in a rectangular or square grid or in concentriccircles. The spacing may depend on numerous factors, including heightand width of the microneedles, as well as the amount and type of anysubstance that is intended to be moved through the microneedles. While avariety of arrangements of microneedles is useful, a particularly usefularrangement of microneedles is a “tip-to-tip” spacing betweenmicroneedles of about 50 micrometers or more, in some embodiments about100 to about 800 micrometers, and in some embodiments, from about 200 toabout 600 micrometers.

Referring again to FIG. 1, microneedles may be held on a substrate 20(i.e., attached to or unitary with a substrate) such that they areoriented perpendicular or at an angle to the substrate. In oneembodiment, the microneedles may be oriented perpendicular to thesubstrate and a larger density of microneedles per unit area ofsubstrate may be provided. However, an array of microneedles may includea mixture of microneedle orientations, heights, materials, or otherparameters. The substrate 20 may be constructed from a rigid or flexiblesheet of metal, ceramic, plastic or other material. The substrate 20 canvary in thickness to meet the needs of the device, such as about 1000micrometers or less, in some embodiments from about 1 to about 500micrometers, and in some embodiments, from about 10 to about 200micrometers.

A microneedle surface may define a nanotopography thereon in a random ororganized pattern. FIG. 3 schematically illustrates the ends of tworepresentative microneedles 22. Microneedles 22 define a central bore 24as may be used for delivery of an agent via the microneedles 22. Thesurface 25 of microneedles 22 define nanotopography 26. In thisparticular embodiment, the nanotopography 26 defines a random pattern onthe surface 25 of the microneedle 22.

A microneedle may include a plurality of identical structures formed ona surface or may include different structures formed of various sizes,shapes and combinations thereof. A predetermined pattern of structuresmay include a mixture of structures having various lengths, diameters,cross-sectional shapes, and/or spacings between the structures. Forexample, the structures may be spaced apart in a uniform manner, such asin a rectangular or square grid or in concentric circles. In oneembodiment, structures may vary with regard to size and/or shape and mayform a complex nanotopography. For example, a complex nanotopography maydefine a fractal or fractal-like geometry.

As utilized herein, the term “fractal” generally refers to a geometricor physical structure having a fragmented shape at all scales ofmeasurement between a greatest and a smallest scale such that certainmathematical or physical properties of the structure behave as if thedimensions of the structure are greater than the spatial dimensions.Mathematical or physical properties of interest may include, forexample, the perimeter of a curve or the flow rate in a porous medium.The geometric shape of a fractal may be split into parts, each of whichdefines self-similarity. Additionally, a fractal has a recursivedefinition and has a fine structure at arbitrarily small scales.

As utilized herein, the term “fractal-like” generally refers to ageometric or physical structure having one or more, but not all, of thecharacteristics of a fractal. For instance, a fractal-like structure mayinclude a geometric shape that includes self-similar parts, but may notinclude a fine structure at an arbitrarily small scale. In anotherexample, a fractal-like geometric shape or physical structure may notdecrease (or increase) in scale equally between iterations of scale, asmay a fractal, though it will increase or decrease between recursiveiterations of a geometric shape of the pattern. A fractal-like patternmay be simpler than a fractal. For instance, it may be regular andrelatively easily described in traditional Euclidean geometric language,whereas a fractal may not.

A microneedle surface defining a complex nanotopography may includestructures of the same general shape (e.g., pillars) and the pillars maybe formed to different scales of measurement (e.g., nano-scale pillarsas well as micro-scale pillars). In another embodiment, a microneedlemay include at a surface structures that vary in both scale size andshape or that vary only in shape while formed to the same nano-sizedscale. Additionally, structures may be formed in an organized array orin a random distribution. In general, at least a portion of thestructures may be nanostructures formed on a nano-sized scale, e.g.,defining a cross-sectional dimension of less than about 500 nanometers,for instance less than about 400 nanometers, less than about 250nanometers, or less than about 100 nanometers. The cross sectionaldimension of the nanostructures can generally be greater than about 5nanometers, for instance greater than about 10 nanometers, or greaterthan about 20 nanometers. For example, the nanostructures can define across sectional dimension between about 5 nanometers and about 500nanometers, between about 20 nanometers and about 400 nanometers, orbetween about 100 nanometers and about 300 nanometers. In cases wherethe cross sectional dimension of a nanostructure varies as a function ofheight of the nanostructure, the cross sectional dimension can bedetermined as an average from the base to the tip of the nanostructures,or as the maximum cross sectional dimension of the structure, forexample the cross sectional dimension at the base of a cone-shapednanostructure.

FIG. 4 illustrates one embodiment of a complex nanotopography as may beformed on a surface. This particular pattern includes a central largepillar 100 and surrounding pillars 102, 104, of smaller dimensionsprovided in a regular pattern. As may be seen, this pattern includes aniteration of pillars, each of which is formed with the same generalshape, but vary with regard to horizontal dimension. This particularcomplex pattern is an example of a fractal-like pattern that does notinclude identical alteration in scale between successive recursiveiterations. For example, while the pillars 102 are first nanostructuresthat define a horizontal dimension that is about one third that of thelarger pillar 100, which is a microstructure, the pillars 104 are secondnanostructures that define a horizontal dimension that is about one halfthat of the pillars 102.

A pattern that includes structures of different sizes can include largerstructures having a cross-sectional dimension formed on a larger scale,e.g., microstructures having a cross-sectional dimension greater thanabout 500 nanometers in combination with smaller nanostructures. In oneembodiment, microstructures of a complex nanotopography can have across-sectional dimension between about 500 nanometers and about 10micrometers, between about 600 nanometers and about 1.5 micrometers, orbetween about 650 nanometers and about 1.2 micrometers. For example, thecomplex nanotopography of FIG. 4 includes micro-sized pillars 100 havinga cross sectional dimension of about 1.2 micrometers.

When a pattern includes one or more larger microstructures, forinstance, having a cross-sectional dimension greater than about 500nanometers, determined either as the average cross sectional dimensionof the structure or as the largest cross sectional dimension of thestructure, the complex nanotopography will also include nanostructures,e.g., first nanostructures, second nanostructures of a different sizeand/or shape, etc. For example, pillars 102 of the complexnanotopography of FIG. 4 have a cross-sectional dimension of about 400nanometers, and pillars 104 have a cross-sectional dimension of about200 nanometers.

A nanotopography can be formed of any number of different elements. Forinstance, a pattern of elements can include two different elements,three different elements, an example of which is illustrated in FIG. 4,four different elements, or more. The relative proportions of therecurrence of each different element can also vary. In one embodiment,the smallest elements of a pattern will be present in larger numbersthan the larger elements. For instance in the pattern of FIG. 4, thereare eight pillars 104 for each pillar 102, and there are eight pillars102 for the central large pillar 100. As elements increase in size,there can generally be fewer recurrences of the element in thenanotopography. By way of example, a first element that is about 0.5times, for instance between about 0.3 times and about 0.7 times incross-sectional dimension as a second, larger element can be present inthe topography about five times or more than the second element. A firstelement that is approximately 0.25 times, or between about 0.15 timesand about 0.3 times in cross-sectional dimension as a second, largerelement can be present in the topography about 10 times or more than thesecond element.

The spacing of individual elements can also vary. For instance,center-to-center spacing of individual structures can be between about50 nanometers and about 1 micrometer, for instance between about 100nanometers and about 500 nanometers. For example, center-to-centerspacing between structures can be on a nano-sized scale. For instance,when considering the spacing of nano-sized structures, thecenter-to-center spacing of the structures can be less than about 500nanometers. This is not a requirement of a topography, however, andindividual structures can be farther apart. The center-to-center spacingof structures can vary depending upon the size of the structures. Forexample, the ratio of the average of the cross-sectional dimensions oftwo adjacent structures to the center-to-center spacing between thosetwo structures can be between about 1:1 (e.g., touching) and about 1:4,between about 1:1.5 and about 1:3.5, or between about 1:2 and about 1:3.For instance, the center to center spacing can be approximately doublethe average of the cross-sectional dimensions of two adjacentstructures. In one embodiment, two adjacent structures each having across-sectional dimension of about 200 nanometers can have acenter-to-center spacing of about 400 nanometers. Thus, the ratio of theaverage of the diameters to the center-to-center spacing in this case is1:2.

Structure spacing can be the same, i.e., equidistant, or can vary forstructures in a pattern. For instance, the smallest structures of apattern can be spaced apart by a first distance, and the spacing betweenthese smallest structures and a larger structure of the pattern orbetween two larger structures of the pattern can be the same ordifferent as this first distance.

For example, in the pattern of FIG. 4, the smallest structures 104 havea center-to-center spacing of about 200 nanometers. The distance betweenthe larger pillars 102 and each surrounding pillar 104 is less, about100 nanometers. The distance between the largest pillar 100 and eachsurrounding pillar 104 is also less than the center-to-center spacingbetween to smallest pillars 104, about 100 nanometers. Of course, thisis not a requirement, and all structures can be equidistant from oneanother or any variation in distances. In one embodiment, differentstructures can be in contact with one another, for instance atop oneanother, as discussed further below, or adjacent one another and incontact with one another.

Structures of a topography may all be formed to the same height,generally between about 10 nanometers and about 1 micrometer, but thisis not a requirement, and individual structures of a pattern may vary insize in one, two, or three dimensions. In one embodiment, some or all ofthe structures of a topography can have a height of less than about 20micrometers, less than about 10 micrometers, or less than about 1micrometer, for instance less than about 750 nanometers, less than about680 nanometers, or less than about 500 nanometers. For instance thestructures can have a height between about 50 nanometers and about 20micrometers or between about 100 nanometers and about 700 nanometers.For example, nanostructures or microstructures can have a height betweenabout 20 nm and about 500 nm, between about 30 nm and about 300 nm, orbetween about 100 nm and about 200 nm, though it should be understoodthat structures may be nano-sized in a cross sectional dimension and mayhave a height that may be measured on a micro-sized scale, for instancegreater than about 500 nm. Micro-sized structures can have a height thatis the same or different from nano-sized structures of the same pattern.For instance, micro-sized structures can have a height of between about500 nanometers and about 20 micrometers, or between about 1 micrometerand about 10 micrometers, in another embodiment. Micro-sized structuresmay also have a cross sectional dimension on a micro-scale greater thanabout 500 nm, and may have a height that is on a nano-sized scale ofless than about 500 nm.

The aspect ratio of the structures (the ratio of the height of astructure to the cross sectional dimension of the structure) can bebetween about 0.15 and about 30, between about 0.2 and about 5, betweenabout 0.5 and about 3.5, or between about 1 and about 2.5. For instance,the aspect ratio of the nanostructures may fall within these ranges.

The device surface may include a single instance of a pattern, as shownin FIG. 4, or may include multiple iterations of the same or differentpatterns. For example, FIG. 5 illustrates a surface pattern includingthe pattern of FIG. 4 in multiple iterations over a surface.

The formation of nanotopography on a surface may increase the surfacearea without a corresponding increase in volume. Increase in the surfacearea to volume ratio is believed to improve the interaction of a surfacewith surrounding biological materials. For instance, increase in thesurface area to volume ratio is believed to encourage mechanicalinteraction between the nanotopography and surrounding proteins, e.g.,extracellular matrix (ECM) proteins and/or plasma membrane proteins.

In general, the surface area to volume ratio of the device may begreater than about 10,000 cm⁻¹, greater than about 150,000 cm⁻¹, orgreater than about 750,000 cm⁻¹. Determination of the surface area tovolume ratio may be carried out according to any standard methodology asis known in the art. For instance, the specific surface area of asurface may be obtained by the physical gas adsorption method (B.E.T.method) with nitrogen as the adsorption gas, as is generally known inthe art and described by Brunauer, Emmet, and Teller (J. Amer. Chem.Soc., vol. 60, February, 1938, pp. 309-319), incorporated herein byreference. The BET surface area can be less than about 5 m²/g, in oneembodiment, for instance between about 0.1 m²/g and about 4.5 m²/g, orbetween about 0.5 m²/g and about 3.5 m²/g. Values for surface area andvolume may also be estimated from the geometry of molds used to form asurface, according to standard geometric calculations. For example, thevolume can be estimated according to the calculated volume for eachpattern element and the total number of pattern elements in a givenarea, e.g., over the surface of a single microneedle.

For a device that defines a complex pattern nanotopography at a surface,the nanotopography may be characterized through determination of thefractal dimension of the pattern. The fractal dimension is a statisticalquantity that gives an indication of how completely a fractal appears tofill space as the recursive iterations continue to smaller and smallerscale. The fractal dimension of a two dimensional structure may berepresented as:

$D = \frac{\log \; {N(e)}}{\log (e)}$

where N(e) is the number of self-similar structures needed to cover thewhole object when the object is reduced by 1/e in each spatialdirection.

For example, when considering the two dimensional fractal known as theSierpenski triangle illustrated in FIG. 6, in which the mid-points ofthe three sides of an equilateral triangle are connected and theresulting inner triangle is removed, the fractal dimension is calculatedas follows:

$D = \frac{\log \; {N(e)}}{\log (e)}$$D = \frac{\log \; 3}{\log \mspace{11mu} 2}$ D ≈ 1.585

Thus, the Sierpenski triangle fractal exhibits an increase in linelength over the initial two dimensional equilateral triangle.Additionally, this increase in line length is not accompanied by acorresponding increase in area.

The fractal dimension of the pattern illustrated in FIG. 4 isapproximately 1.84. In one embodiment, nanotopography of a surface ofthe device may exhibit a fractal dimension of greater than about 1, forinstance between about 1.2 and about 5, between about 1.5 and about 3,or between about 1.5 and about 2.5.

FIGS. 7A and 7B illustrate increasing magnification images of anotherexample of a complex nanotopography. The nanotopography of FIGS. 7A and7B includes an array of fibrous-like pillars 70 located on a substrate.At the distal end of each individual pillar, the pillar splits intomultiple smaller fibers 60. At the distal end of each of these smallerfibers 60, each fiber splits again into multiple filaments (not visiblein FIGS. 7A and 7B). Structures formed on a surface that have an aspectratio greater than about 1 may be flexible, as are the structuresillustrated in FIGS. 7A and 7B, or may be stiff.

FIGS. 7C and 7D illustrate another example of a complex nanotopography.In this embodiment, a plurality of pillars 72 each including an annularhollow therethrough 71 are formed on a substrate. At the distal end ofeach hollow pillar, a plurality of smaller pillars 62 is formed. As maybe seen, the pillars of FIGS. 7C and 7D maintain their stiffness andupright orientation. Additionally, and in contrast to previous patterns,the smaller pillars 62 of this embodiment differ in shape from thelarger pillars 72. Specifically, the smaller pillars 62 are not hollow,but are solid. Thus, nanotopography including structures formed to adifferent scale need not have all structures formed with the same shape,and structures may vary in both size and shape from the structures of adifferent scale.

FIG. 8 illustrates another pattern including nano-sized structures asmay be formed on the device surface. As may be seen, in this embodiment,individual pattern structures may be formed at the same general size,but with different orientations and shapes from one another.

In addition to or alternative to those methods mentioned above, asurface may be characterized by other methods including, withoutlimitation, surface roughness, elastic modulus, and surface energy.

Methods for determining the surface roughness are generally known in theart. For instance, an atomic force microscope process in contact ornon-contact mode may be utilized according to standard practice todetermine the surface roughness of a material. Surface roughness thatmay be utilized to characterize a microneedle can include the averageroughness (R_(A)), the root mean square roughness, the skewness, and/orthe kurtosis. In general, the average surface roughness (i.e., thearithmetical mean height of the surface are roughness parameter asdefined in the ISO 25178 series) of a surface defining a fabricatednanotopography thereon may be less than about 200 nanometers, less thanabout 190 nanometers, less than about 100 nanometers, or less than about50 nanometers. For instance, the average surface roughness may bebetween about 10 nanometers and about 200 nanometers, or between about50 nanometers and about 190 nanometers.

The device may be characterized by the elastic modulus of thenanopatterned surface, for instance by the change in elastic modulusupon the addition of a nanotopography to a surface. In general, theaddition of a plurality of structures forming nanotopography on asurface can decrease the elastic modulus of a material, as the additionof nano-sized structures on a surface will lead to a reduction incontinuity of the surface and a related change in surface area. Ascompared to a similar surface formed according to the same process andof the same materials, but for a pattern of nanotopography on thesurface, the device including nanotopography thereon can exhibit adecrease in elastic modulus of between about 35% and about 99%, forinstance between about 50% and about 99%, or between about 75% and about80%. By way of example, the effective compression modulus of ananopatterned surface can be less than about 50 MPa, or less than about20 MPa. In one embodiment the effective compression modulus can bebetween about 0.2 MPa and about 50 MPa, between about 5 MPa and about 35MPa, or between about 10 MPa and about 20 MPa. The effective shearmodulus can be less than about 320 MPa, or less than about 220 MPa. Forinstance, the effective shear modulus can be between about 4 MPa andabout 320 MPa, or between about 50 MPa and about 250 MPa, in oneembodiment.

The device including nanotopography thereon may also exhibit an increasein surface energy as compared to a similar microneedle that does nothave a surface defining a pattern of nanotopography thereon. Forinstance, a microneedle including a nanotopography formed thereon canexhibit an increase in surface energy as compared to a similarmicroneedle of the same materials and formed according to the samemethods, but for the inclusion of a pattern of nanotopography on asurface. For instance, the water contact angle of a surface including ananotopography thereon can be greater than about 80° greater than about90° greater than about 100°, or greater than about 110°. For example,the water contact angle of a surface can be between about 80° and about150°, between about 90° and about 130°, or between about 100° and about120°, in one embodiment.

When forming nanostructures on the surface of the device, the packingdensity of the structures may be maximized. For instance, square packing(FIG. 9A), hexagonal packing (FIG. 9B), or some variation thereof may beutilized to pattern the elements on a substrate. When designing apattern in which various sized elements of cross sectional areas A, B,and C are adjacent to one another on a substrate, circle packing asindicated in FIG. 9C may be utilized. Of course, variations in packingdensity and determination of associated alterations in characteristicsof a surface are well within the abilities of one of skill in the art.

The device including a fabricated nanotopography on a surface of thedevice may be formed according to a single-step process. Alternatively,a multi-step process may be used, in which a pattern of nanostructuresare fabricated on a pre-formed surface. For example, an array ofmicroneedles may be first formed and then a random or non-random patternof nanostructures may be fabricated on the surface of the formedmicroneedles. In either the single-step or two-step process, structuresmay be fabricated on a surface or on a mold surface according to anysuitable nanotopography fabrication method including, withoutlimitation, nanoimprinting, injection molding, lithography, embossingmolding, and so forth.

In general, an array of microneedles may be formed according to anystandard microfabrication technique including, without limitation,lithography; etching techniques, such as wet chemical, dry, andphotoresist removal; thermal oxidation of silicon; electroplating andelectroless plating; diffusion processes, such as boron, phosphorus,arsenic, and antimony diffusion; ion implantation; film deposition, suchas evaporation (filament, electron beam, flash, and shadowing and stepcoverage), sputtering, chemical vapor deposition (CVD), epitaxy (vaporphase, liquid phase, and molecular beam), electroplating, screenprinting, lamination, stereolithography, laser machining, and laserablation (including projection ablation).

Lithography techniques, including photolithography, e-beam lithography,X-ray lithography, and so forth may be utilized for primary patterndefinition and formation of a master die. Replication may then becarried out to form the device including an array of microneedles.Common replication methods include, without limitation, solvent-assistedmicromolding and casting, embossing molding, injection molding, and soforth. Self-assembly technologies including phase-separated blockcopolymer, polymer demixing and colloidal lithography techniques mayalso be utilized in forming a nanotopography on a surface.

Combinations of methods may be used, as is known. For instance,substrates patterned with colloids may be exposed to reactive ionetching (RIE, also known as dry etching) so as to refine thecharacteristics of a fabricated nanostructure such as nanopillardiameter, profile, height, pitch, and so forth. Wet etching may also beemployed to produce alternative profiles for fabricated nanostructuresinitially formed according to a different process, e.g., polymerdemixing techniques. Structure diameter, shape, and pitch may becontrolled via selection of appropriate materials and methods.

Other methods as may be utilized in forming a microneedle including afabricated nanotopography on a surface include nanoimprint lithographymethods utilizing ultra-high precision laser machining techniques,examples of which have been described by Hunt, et al. (U.S. Pat. No.6,995,336) and Guo, et al. (U.S. Pat. No. 7,374,864), both of which areincorporated herein by reference. Nanoimprint lithography is anano-scale lithography technique in which a hybrid mold is utilizedwhich acts as both a nanoimprint lithography mold and a photolithographymask. A schematic of a nanoimprint lithography technique is illustratedin FIGS. 10A-10C. During fabrication, a hybrid mold 30 imprints into asubstrate 32 via applied pressure to form features (e.g., microneedlesdefining nanotopography) on a resist layer (FIG. 10A). In general, thesurface of the substrate 32 may be heated prior to engagement with themold 30 to a temperature above its glass transition temperature (T_(g)).While the hybrid mold 30 is engaged with the substrate 32, a flow ofviscous polymer may be forced into the mold cavities to form features 34(FIG. 10B). The mold and substrate may then be exposed to ultravioletlight. The hybrid mold is generally transmissive to UV radiation savefor certain obstructed areas. Thus, the UV radiation passes throughtransmissive portions and into the resist layer. Pressure is maintainedduring cooling of the mold and substrate. The hybrid mold 30 is thenremoved from the cooled substrate 32 at a temperature below T_(g) of thesubstrate and polymer (FIG. 10C).

To facilitate the release of the nanoimprinted substrate 32 includingfabricated features 34 from the mold 30, as depicted in FIG. 10C, it isadvantageous to treat the mold 30 with a low energy coating to reducethe adhesion with the substrate 32, as a lower surface energy of themold 30 and the resulting greater surface energy difference between themold 30, substrate 32, and polymer may ease the release between thematerials. By way of example, a silicon mold coating may be used such astrideca-(1,1,2,2-tetrahydro)-octytrichloro silane (F₁₃-TCS).

Structures may also be formed according to chemical addition processes.For instance, film deposition, sputtering, chemical vapor deposition(CVD); epitaxy (vapor phase, liquid phase, and molecular beam),electroplating, and so forth can be utilized for building structures ona surface. Self-assembled monolayer processes as are known in the artcan be utilized to form a pattern of structures on a surface.

The surface of a transdermal delivery device can be furtherfunctionalized for improved interaction with tissues or individual cellsduring use. For instance, one or more biomolecules such aspolynucleotides, polypeptides, entire proteins, polysaccharides, and thelike can be bound to a structured surface prior to use.

In some embodiments, a surface including structures formed thereon canalready contain suitable reactivity such that additional desiredfunctionality may spontaneously attach to the surface with nopretreatment of the surface necessary. However, in other embodiments,pretreatment of the structured surface prior to attachment of thedesired compound may be carried out. For instance, reactivity of astructure surface may be increased through addition or creation ofamine, carboxylic acid, hydroxy, aldehyde, thiol, or ester groups on thesurface. In one representative embodiment, a microneedle surfaceincluding a pattern of nanostructures formed thereon may be aminatedthrough contact with an amine-containing compound such as3-aminopropyltriethoxy silane in order to increase the aminefunctionality of the surface and bind one or more biomolecules to thesurface via the added amine functionality.

Materials as may be desirably bound to the surface of a patterned devicecan include ECM proteins such as laminins, tropoelastin or elastin,Tropocollagen or collagen, fibronectin, and the like. Short polypeptidefragments can be bound to the surface of a patterned device such as anRGD sequence, which is part of the recognition sequence of integrinbinding to many ECM proteins. Thus, functionalization of a microneedlesurface with RGD can encourage interaction of the device with ECMproteins and further limit foreign body response to the device duringuse.

The transdermal delivery device may be in the form of a patch that mayinclude various features. For example, the device may include areservoir, e.g., a vessel, a porous matrix, etc., that may store andagent and provide the agent for delivery. The device may include areservoir within the device itself. For instance, the device may includea hollow, or multiple pores that may carry one or more agents fordelivery. The agent may be released from the device via degradation of aportion or the entire device or via diffusion of the agent from thedevice.

FIGS. 11A and 11B are perspective views of the device including areservoir. The device 110 includes a reservoir 112 defined by animpermeable backing layer 114 and a microneedle array 116. The backinglayer and the microneedle array 116 are joined together about the outerperiphery of the device, as indicated at 118. The impermeable backinglayer 114 may be joined by an adhesive, a heat seal or the like. Thedevice 110 also includes a plurality of microneedles 120. A releaseliner 122 can be removed prior to use of the device to exposemicroneedles 120.

A formulation including one or more agents may be retained within thereservoir 112. Materials suitable for use as impermeable backing layer114 can include materials such as polyesters, polyethylene,polypropylene and other synthetic polymers. The material is generallyheat or otherwise sealable to the backing layer to provide a barrier totransverse flow of reservoir contents.

Reservoir 112, defined by the space or gap between the impermeablebacking layer 114 and the microneedle array 116, provides a storagestructure in which to retain the suspension of agents to beadministered. The reservoir may be formed from a variety of materialsthat are compatible with an agent to be contained therein. By way ofexample, natural and synthetic polymers, metals, ceramics, semiconductormaterials, and composites thereof may form the reservoir.

In one embodiment, the reservoir may be attached to the substrate uponwhich the microneedles are located. According to another embodiment, thereservoir may be separate and removably connectable to the microneedlearray or in fluid communication with the microneedle array, for instancevia appropriate tubing, leur locks, etc.

The device may include one or a plurality of reservoirs for storingagents to be delivered. For instance, the device may include a singlereservoir that stores a single or multiple agent-containing formulation,or the device may include multiple reservoirs, each of which stores oneor more agents for delivery to all or a portion of the array ofmicroneedles. Multiple reservoirs may each store a different materialthat may be combined for delivery. For instance, a first reservoir maycontain an agent, e.g., a drug, and a second reservoir may contain avehicle, e.g., saline. The different agents may be mixed prior todelivery. Mixing may be triggered by any means, including, for example,mechanical disruption (i.e. puncturing, degradation, or breaking),changing the porosity, or electrochemical degradation of the walls ormembranes separating the chambers. Multiple reservoirs may containdifferent active agents for delivery that may be delivered inconjunction with one another or sequentially.

In one embodiment, the reservoir may be in fluid communication with oneor more microneedles of the transdermal device, and the microneedles maydefine a structure (e.g., a central or lateral bore) to allow transportof delivered agents beneath the barrier layer.

In alternative embodiments, a device may include a microneedle assemblyand a reservoir assembly with flow prevention between the two prior touse. For instance, a device may include a release member positionedadjacent to both a reservoir and a microneedle array. The release membermay be separated from the device prior to use such that during use thereservoir and the microneedle array are in fluid communication with oneanother. Separation may be accomplished through the partial or completedetachment of the release member. For example, referring to FIGS. 12-17,one embodiment of a release member is shown that is configured to bedetached from a transdermal patch to initiate the flow of a drugcompound. More particularly, FIGS. 12-17 show a transdermal patch 300that contains a drug delivery assembly 370 and a microneedle assembly380. The drug delivery assembly 370 includes a reservoir 306 positionedadjacent to a rate control membrane 308.

The rate control membrane may help slow down the flow rate of the drugcompound upon its release. Specifically, fluidic drug compounds passingfrom the drug reservoir to the microneedle assembly via microfluidicchannels may experience a drop in pressure that results in a reductionin flow rate. If this difference is too great, some backpressure may becreated that may impede the flow of the compound and potentiallyovercome the capillary pressure of the fluid through the microfluidicchannels. Thus, the use of the rate control membrane may ameliorate thisdifference in pressure and allow the drug compound to be introduced intothe microneedle at a more controlled flow rate. The particularmaterials, thickness, etc. of the rate control membrane may vary basedon multiple factors, such as the viscosity of the drug compound, thedesired delivery time, etc.

The rate control membrane may be fabricated from permeable,semi-permeable or microporous materials that are known in the art tocontrol the rate of drug compounds and having permeability to thepermeation enhancer lower than that of drug reservoir. For example, thematerial used to form the rate control membrane may have an average poresize of from about 50 nanometers to about 5 micrometers, in someembodiments from about 100 nanometers to about 2 micrometers, and insome embodiments, from about 300 nanometers to about 1 micrometer (e.g.,about 600 nanometers). Suitable membrane materials include, forinstance, fibrous webs (e.g., woven or nonwoven), apertured films,foams, sponges, etc., which are formed from polymers such aspolyethylene, polypropylene, polyvinyl acetate, ethylene n-butyl acetateand ethylene vinyl acetate copolymers. Such membrane materials are alsodescribed in more detail in U.S. Pat. Nos. 3,797,494, 4,031,894,4,201,211, 4,379,454, 4,436,741, 4,588,580, 4,615,699, 4,661,105,4,681,584, 4,698,062, 4,725,272, 4,832,953, 4,908,027, 5,004,610,5,310,559, 5,342,623, 5,344,656, 5,364,630, and 6,375,978, which areincorporated in their entirety herein by reference for all relevantpurposes. A particularly suitable membrane material is available fromLohmann Therapie-Systeme.

Referring to FIGS. 12-13, although optional, the assembly 370 alsocontains an adhesive layer 304 that is positioned adjacent to thereservoir 306. The microneedle assembly 380 likewise includes a support312 from which extends a plurality of microneedles 330 having channels331, such as described above. The layers of the drug delivery assembly370 and/or the microneedle assembly 380 may be attached together ifdesired using any known bonding technique, such as through adhesivebonding, thermal bonding, ultrasonic bonding, etc.

Regardless of the particular configuration employed, the patch 300 alsocontains a release member 310 that is positioned between the drugdelivery assembly 370 and the microneedle assembly 380. While therelease member 310 may optionally be bonded to the adjacent support 312and/or rate control membrane 308, it is typically desired that it isonly lightly bonded, if at all, so that the release member 310 may beeasily withdrawn from the patch 300. If desired, the release member 310may also contain a tab portion 371 (FIGS. 12-13) that extends at leastpartly beyond the perimeter of the patch 300 to facilitate the abilityof a user to grab onto the member and pull it in the desired direction.In its “inactive” configuration as shown in FIGS. 12-13, the drugdelivery assembly 370 of the patch 300 securely retains a drug compound307 so that it does not flow to any significant extent into themicroneedles 330. The patch may be “activated” by simply applying aforce to the release member so that it is detached from the patch.

Referring to FIGS. 14-15, one embodiment for activating the patch 300 isshown in which the release member 310 is pulled in a longitudinaldirection. The entire release member 310 may be removed as shown inFIGS. 16-17, or it may simply be partially detached as shown in FIGS.14-15. In either case, however, the seal previously formed between therelease member 310 and the aperture (not shown) of the support 312 isbroken. In this manner, a drug compound 107 may begin to flow from thedrug delivery assembly 170 and into the channels 131 of the microneedles130 via the support 112. An exemplary illustration of how the drugcompound 307 flows from the reservoir 306 and into the channels 331 isshown in FIGS. 16-17. Notably, the flow of the drug compound 307 ispassively initiated and does not require any active displacementmechanisms (e.g., pumps).

In the embodiments shown in FIGS. 12-17, the detachment of the releasemember immediately initiates the flow of the drug compound to themicroneedles because the drug delivery assembly is already disposed influid communication with the microneedle assembly. In certainembodiments, however, it may be desired to provide the user with agreater degree of control over the timing of the release of the drugcompound. This may be accomplished by using a patch configuration inwhich the microneedle assembly is not initially in fluid communicationwith the drug delivery assembly. When it is desired to use the patch,the user may physically manipulate the two separate assemblies intofluid communication. The release member may be separated either beforeor after such physical manipulation occurs.

Referring to FIGS. 18-23, for example, one particular embodiment of apatch 200 is shown. FIGS. 18-19 illustrate the patch 200 before use, andshows a first section 250 formed by a microneedle assembly 280 and asecond section 260 formed by a drug delivery assembly 270. The drugdelivery assembly 270 includes a reservoir 206 positioned adjacent to arate control membrane 208 as described above. Although optional, theassembly 270 also contains an adhesive layer 204 that is positionedadjacent to the reservoir 206. The microneedle assembly 280 likewiseincludes a support 212 from which extends a plurality of microneedles230 having channels 231, such as described above.

In this embodiment, the support 212 and the rate control membrane 208are initially positioned horizontally adjacent to each other, and arelease member 210 extends over the support 212 and the rate controlmember 208. In this particular embodiment, it is generally desired thatthe release member 210 is releasably attached to the support 212 and therate control membrane 208 with an adhesive (e.g., pressure-sensitiveadhesive). In its “inactive” configuration as shown in FIGS. 18-19, thedrug delivery assembly 270 of the patch 200 securely retains a drugcompound 207 so that it does not flow to any significant extent into themicroneedles 230. When it is desired to “activate” the patch, therelease member 210 may be peeled away and removed, such as illustratedin FIGS. 20-21, to break the seal previously formed between the releasemember 210 and the aperture (not shown) of the support 212. Thereafter,the second section 260 may be folded about a fold line “F” as shown bythe directional arrow in FIG. 22 so that the rate control member 208 ispositioned vertically adjacent to the support 212 and in fluidcommunication therewith. Alternatively, the first section 250 may befolded. Regardless, folding of the sections 250 and/or 260 initiates theflow of a drug compound 207 from the drug delivery assembly 270 and intothe channels 231 of the microneedles 230 via the support 212 (See FIG.23).

The device may deliver an agent at a rate so as to be therapeuticallyuseful. In accord with this goal, a transdermal device may include ahousing with microelectronics and other micro-machined structures tocontrol the rate of delivery either according to a preprogrammedschedule or through active interface with the patient, a healthcareprofessional, or a biosensor. The device may include a material at asurface having a predetermined degradation rate, so as to controlrelease of an agent contained within the device. A delivery rate may becontrolled by manipulating a variety of factors, including thecharacteristics of the formulation to be delivered (e.g., viscosity,electric charge, and/or chemical composition); the dimensions of eachdevice (e.g., outer diameter and the volume of any openings); the numberof microneedles on a transdermal patch; the number of individual devicesin a carrier matrix; the application of a driving force (e.g., aconcentration gradient, a voltage gradient, a pressure gradient); theuse of a valve; and so forth.

Transportation of agents through the device may be controlled ormonitored using, for example, various combinations of valves, pumps,sensors, actuators, and microprocessors. These components may beproduced using standard manufacturing or microfabrication techniques.Actuators that may be useful with the device may include micropumps,microvalves, and positioners. For instance, a microprocessor may beprogrammed to control a pump or valve, thereby controlling the rate ofdelivery.

Flow of an agent through the device may occur based on diffusion orcapillary action, or may be induced using conventional mechanical pumpsor nonmechanical driving forces, such as electroosmosis orelectrophoresis, or convection. For example, in electroosmosis,electrodes are positioned on a biological surface (e.g., the skinsurface), a microneedle, and/or a substrate adjacent a microneedle, tocreate a convective flow which carries oppositely charged ionic speciesand/or neutral molecules toward or into the delivery site.

Flow of an agent may be manipulated by selection of the material formingthe microneedle surface. For example, one or more large grooves adjacentthe microneedle surface of the device may be used to direct the passageof drug, particularly in a liquid state. Alternatively, the physicalsurface properties of the device may be manipulated to either promote orinhibit transport of material along the surface, such as by controllinghydrophilicity or hydrophobicity.

The flow of an agent may be regulated using valves or gates as is knownin the art. Valves may be repeatedly opened and closed, or they may besingle-use valves. For example, a breakable barrier or one-way gate maybe installed in the device between a reservoir and the patternedsurface. When ready to use, the barrier may be broken or gate opened topermit flow through to the microneedle surface. Other valves or gatesused in the device may be activated thermally, electrochemically,mechanically, or magnetically to selectively initiate, modulate, or stopthe flow of molecules through the device. In one embodiment, flow iscontrolled by using a rate-limiting membrane as a “valve.”

In general, any agent delivery control system, including reservoirs,flow control systems, sensing systems, and so forth as are known in theart may be incorporated with devices. By way of example, U.S. Pat. Nos.7,250,037, 7,315,758, 7,429,258, 7,582,069, and 7,611,481 describereservoir and control systems as may be incorporated in devices.

The subject matter may be better understood with reference to theExamples, presented below.

Example 1

Several different molds were prepared using photolithography techniquessimilar to those employed in the design and manufacture of electricalcircuits. Individual process steps are generally known in the art andhave been described Initially, silicon substrates were prepared bycleaning with acetone, methanol, and isopropyl alcohol, and then coatedwith a 258 nanometer (nm) layer of silicon dioxide according to achemical vapor deposition process.

A pattern was then formed on each substrate via an electron beamlithography patterning process as is known in the art using a JEOLJBX-9300FS EBL system. The processing conditions were as follows:

Beam current=11 nA

Acceleration voltage=100 kV

Shot pitch=14 nm

Dose=260 μC/cm²

Resist=ZEP520A, ˜330 nm thickness

Developer=n-amyl acetate

Development=2 min. immersion, followed by 30 sec. isopropyl alcoholrinse.

A silicon dioxide etch was then carried out with an STS Advanced OxideEtch (AOE). Etch time was 50 seconds utilizing 55 standard cubiccentimeters per minute (sccm) He, 22 sccm CF₄, 20 sccm C₄F₈ at 4 mTorr,400 W coil, 200 W RIE and a DC Bias of 404-411 V.

Following, a silicon etch was carried out with an STS silicon oxide etch(SOE). Etch time was 2 minutes utilizing 20 sccm Cl₂ and 5 sccm Ar at 5mTorr, 600 W coil, 50 W RIE and a DC Bias of 96-102 V. The silicon etchdepth was 500 nanometers.

A buffered oxide etchant (BOE) was used for remaining oxide removal thatincluded a three minute BOE immersion followed by a deionized waterrinse.

An Obducat NIL-Eitre®6 nanoimprinter was used to form nanopatterns on avariety of polymer substrates. External water was used as coolant. TheUV module utilized a single pulsed lamp at a wave length of between 200and 1000 nanometers at 1.8 W/cm². A UV filter of 250-400 nanometers wasused. The exposure area was 6 inches with a maximum temperature of 200°C. and 80 Bar. The nanoimprinter included a semi-automatic separationunit and automatic controlled demolding.

To facilitate the release of the nanoimprinted films from the molds, themolds were treated with Trideca-(1,1,2,2-tetrahydro)-octytrichlorosilane(F₁₃-TCS). To treat a mold, the silicon mold was first cleaned with awash of acetone, methanol, and isopropyl alcohol and dried with anitrogen gas. A Petri dish was placed on a hot plate in a nitrogenatmosphere and 1-5 ml of the F₁₃-TCS was added to the Petri dish. Asilicon mold was placed in the Petri dish and covered for 10-15 minutesto allow the F₁₃-TCS vapor to wet out the silicon mold prior to removalof the mold.

Five different polymers as given in Table 1, below, were utilized toform various nanotopography designs.

TABLE 1 Surface Glass Transition Tensile Tension Temperature, Modulus(mN/m) Polymer T_(g)(K) (MPa) @20° C. Polyethylene 140-170 100-300 30Polypropylene 280 1,389 21 PMMA 322 3,100 41 Polystyrene 373 3,300 40Polycarbonate 423 2,340 43

Several different nanotopography patterns were formed, schematicrepresentations of which are illustrated in FIGS. 24A-24D. Thenanotopography pattern illustrated in FIG. 24E was a surface of a flatsubstrate purchased from NTT Advanced Technology of Tokyo, Japan. Thepatterns were designated DN1 (FIG. 24A), DN2 (FIG. 24B), DN3 (FIG. 24C),DN4 (FIG. 24D) and NTTAT2 (FIG. 24E). SEM images of the molds are shownin FIGS. 24A, 24B, and 24C, and images of the films are shown in FIGS.24D and 24E. FIG. 8 illustrates a nanopatterned film formed by use ofthe mold of FIG. 24A (DN1). In this particular film, the polymerfeatures were drawn by temperature variation as previously discussed.The surface roughness of the pattern of FIG. 24E was found to be 34nanometers.

The pattern illustrated in FIGS. 7C and 7D was also formed according tothis nanoimprinting process. This pattern included the pillars 72 andpillars 62, as illustrated. Larger pillars 72 were formed with a 3.5micrometer (μm) diameter and 30 μm heights with center-to-center spacingof 6.8 μm. Pillars 62 were 500 nanometers in height and 200 nanometersin diameter and a center-to-center spacing of 250 nanometers.

The nanoimprinting process conditions used with polypropylene films areprovided below in Table 2.

TABLE 2 Time (s) Temperature (C.) Pressure (Bar) 10 50 10 10 75 20 10100 30 420 160 40 180 100 40 180 50 40 180 25 40

Example 2

Films were formed as described above in Example 1 including variousdifferent patterns and formed of either polystyrene (PS) orpolypropylene (PP). The underlying substrate varied in thickness.Patterns utilized were DN2, DN3, or DN4 utilizing formation processes asdescribed in Example 1. The pattern molds were varied with regard tohole depth and feature spacing to form a variety of differently-sizedfeatures having the designated patterns. Sample no. 8 (designated BB 1)was formed by use of a 0.6 μm millipore polycarbonate filter as a mold.A 25 μm polypropylene film was laid over the top of the filter and wasthen heated to melt such that the polypropylene could flow into thepores of the filter. The mold was then cooled and the polycarbonate molddissolved by use of a methylene chloride solvent.

SEMs of the formed films are shown in FIGS. 25-33 and thecharacteristics of the formed films are summarized in Table 3, below.

TABLE 3 Film Cross Surface Water Sample thickness Pattern SectionalFeature Aspect Roughness Fractal Contact No. FIG. Pattern Material (μm)Feature¹ Dimension² height³ Ratio (nm) Dimension Angle 1 25 DN3 PS 75 A1100 nm 520 nm 0.47 150 2.0 100° B 400 nm 560 nm 1.4 C 200 nm 680 nm 3.42  26A, DN2 PP 5.0 n/a 200 nm 100 nm 0.5 16 2.15  91°  26 B 3 27 DN2 PS75 n/a 200 nm 1.0 μm 5 64 2.2 110° 4 28 DN2 PP 25.4 n/a 200 nm 300 nm1.5 38 1.94 118° 5 29 DN3 PS 75 A 1100 nm 570 nm 0.52 21.1 1.98 100° B400 nm 635 nm 1.6 C 200 nm — — 6 30 DN4 PS 75 n/a 200 nm — — 30.6 2.04 80° 7 31 DN4 PP 25.4 n/a 200 nm — — 21.4 2.07 112° 8 32 BB1 PP 25.4 n/a600 nm 18 μm 30 820 2.17 110° 9 33 DN3 PP 5 A 1100 nm 165 nm 0.15 502.13 — B 400 nm 80 nm 0.2 C 200 nm 34 nm 0.17

For each sample AFM was utilized to characterize the film.Characterizations included formation of scanning electron micrograph(SEM), determination of surface roughness, determination of maximummeasured feature height, and determination of fractal dimension.

The atomic force microscopy (AFM) probe utilized was a series 16 siliconprobe and cantilever available from μMasch. The cantilever had aresonant frequency of 170 kHz, a spring constant of 40 N/m, a length of230±5 μm, a width of 40±3 μm, and a thickness of 7.0±0.5 μm. The probetip was an n-type phosphorous-doped silicon probe, with a typical probetip radius of 10 nanometers, a full tip cone angle of 40°, a total tipheight of 20-25 μm, and a bulk resistivity 0.01-0.05 ohm-cm.

The surface roughness value given in Table 4 is the arithmetical meanheight of the surface area roughness parameter as defined in the ISO25178 series.

The Fractal Dimension was calculated for the different angles byanalyzing the Fourier amplitude spectrum; for different angles theamplitude Fourier profile was extracted and the logarithm of thefrequency and amplitude coordinates calculated. The fractal dimension,D, for each direction is then calculated as

D=(6+s)/2

where s is the (negative) slope of the log-log curves. The reportedfractal dimension is the average for all directions.

The fractal dimension can also be evaluated from 2D Fourier spectra byapplication of the Log Log function. If the surface is fractal the LogLog graph should be highly linear, with at negative slope (see, e.g.,Fractal Surfaces, John C. Russ, Springer-Verlag New York, LLC, July,2008).

Example 3

An array of microneedles including a nanopatterned surface was formed.Initially, an array of microneedles as illustrated in FIG. 2 was formedon a silicon wafer via a photolithography process. Each needle includedtwo oppositely placed side channels, aligned with one through-die holein the base of the needle (not visible on FIG. 2).

Microneedles were formed according to a typical micromachining processon a silicon based wafer. The wafers were layered with resist and/oroxide layers followed by selective etching (oxide etching, DRIE etching,iso etching), resist stripping, oxide stripping, and lithographytechniques (e.g., iso lithography, hole lithography, slit lithography)according to standard methods to form the array of microneedles.

Following formation of the microneedle array, a 5 μm polypropylene filmincluding a DN2 pattern formed thereon as described above in Example 1,the characteristics of which are described at sample 2 in Table 4, waslaid over the microneedle array. The wafer/film structure was held on aheated vacuum box (3 inches H₂O vacuum) at elevated temperature (130°C.) for a period of one hour to gently pull the film over the surface ofthe microneedles while maintaining the nanopatterned surface of thefilm.

FIGS. 34A-34D illustrate the film over the top of the array ofmicroneedles, at increasing magnifications.

While the subject matter has been described in detail with respect tothe specific embodiments thereof, it will be appreciated that thoseskilled in the art, upon attaining an understanding of the foregoing,may readily conceive of alterations to, variations of, and equivalentsto these embodiments. Accordingly, the scope of the present disclosureshould be assessed as that of the appended claims and any equivalentsthereto.

1-20. (canceled)
 21. A nanopatterned film comprising: a plurality ofnanostructures, wherein each nanostructure of the plurality ofnanostructures has (i) a cross-sectional dimension less than about 500nanometers and greater than about 5 nanometers and (ii) a height fromabout 10 nanometers to about 1 micrometer; and a plurality ofmicrostructures, wherein each microstructure of the plurality ofmicrostructures has (i) a cross-sectional dimension greater than about500 nanometers and less than about 10 micrometers and (ii) a height fromabout 20 nanometers to about 1 micrometer.
 22. The nanopatterned film ofclaim 21, wherein each nanostructure of the plurality of nanostructureshas a cross-sectional dimension less than about 300 nanometers.
 23. Thenanopatterned film of claim 21, wherein the height of eachmicrostructure of the plurality of microstructures is greater than thecross-sectional dimension of each corresponding microstructure.
 24. Thenanopatterned film of claim 21 wherein the plurality of nanostructuresdefines a plurality of first nanostructures, the film further comprisinga plurality of second nanostructures, wherein each of the plurality ofsecond nanostructures has a cross-sectional dimension less than thecross-sectional dimension of each of the plurality of microstructuresand greater than the cross-sectional dimension of each of the pluralityof first nanostructures.
 25. The nanopatterned film of claim 21, whereineach nanostructure of the plurality of nanostructures has an aspectratio from about 0.5 to about 3.5.
 26. The nanopatterned film of claim21, wherein each nanostructure of the plurality of nanostructures has anaspect ratio from about 0.2 to about
 5. 27. The nanopatterned film ofclaim 21, wherein the plurality of nanostructures has a center-to-centerspacing from about 50 nanometers to about 1 micrometer.
 28. Thenanopatterned film of claim 21, wherein the plurality of nanostructuresand the plurality of microstructures are arranged to have a fractaldimension greater than about
 1. 29. The nanopatterned film of claim 28,wherein the fractal dimension is about 2.5.
 30. The nanopatterned filmof claim 21, wherein a ratio of (i) an average of a cross-sectionaldimension of two adjacent nanostructures of the plurality ofnanostructures to (ii) a center-to-center spacing between the twoadjacent nanostructures is between about 1:1 and about 1:4.
 31. A devicefor delivering a bioactive agent through a stratum corneum to asubdermal location of a user, the device comprising: a microneedlehaving an exterior surface; and a nanopatterned film disposed on theexterior surface of the microneedle, the nanopatterned film comprising:a plurality of nanostructures, each nanostructure of the plurality ofnanostructures having (i) a cross-sectional dimension less than about500 nanometers and greater than about 5 nanometers and (ii) an aspectratio from about 0.2 to about 5; and a plurality of microstructures,each microstructure of the plurality of microstructures having (i) across-sectional dimension greater than about 500 nanometers and lessthan about 10 micrometers and (ii) an aspect ratio from about 0.15 toabout
 5. 32. The device of claim 31 wherein the plurality ofnanostructures defines a plurality of first nanostructures, the devicefurther comprising a plurality of second nanostructures, wherein eachsecond nanostructure of the plurality of second nanostructures has across-sectional dimension less than the cross-sectional dimension ofeach microstructure of the plurality of microstructures and greater thanthe cross-sectional dimension of each nanostructure of the plurality offirst nanostructures.
 33. The device of claim 31, wherein the exteriorsurface of the microneedle has an average surface roughness betweenabout 10 nanometers and about 200 nanometers.
 34. The device of claim31, wherein the exterior surface of the microneedle has an effectiveshear modulus between 4 MPa and 320 MPa.
 35. The device of claim 31,wherein each nanostructure of the plurality of nanostructures has across-sectional dimension from about 20 to about 400 nanometers, andwherein each microstructure of the plurality of microstructures has across-sectional dimension from about 600 nanometers to about 1.5micrometers.
 36. A device for delivering a bioactive agent through astratum corneum to a subdermal location of a user, the devicecomprising: a microneedle having an exterior surface; and ananopatterned film disposed on the exterior surface of the microneedle,the nanopatterned film comprising: a plurality of first nanostructures,wherein each nanostructure of the plurality of first nanostructures has(i) a cross-sectional dimension less than about 500 nanometers andgreater than about 5 nanometers and (ii) an aspect ratio from about 0.2to about 5; a plurality of second nanostructures, wherein each secondnanostructure of the plurality of second nanostructures has across-sectional dimension greater than the cross-sectional dimension ofeach first nanostructure of the plurality of first nanostructures; and aplurality of microstructures, wherein each microstructure of theplurality of microstructures has a cross-sectional dimension greaterthan (i) the cross-sectional dimension of each first nanostructure ofthe plurality of first nanostructures and (ii) the cross-sectionaldimension of each second nanostructure of the plurality of secondnanostructures.
 37. The device of claim 36, wherein each microstructureof the plurality of microstructures has (i) a cross-sectional dimensiongreater than about 500 nanometers and less than about 10 micrometers and(ii) a height from about 20 nanometers to about 1 micrometer.
 38. Thedevice of claim 36, wherein the plurality of first nanostructures, theplurality of second nanostructures, and the plurality of microstructuresare arranged to have a fractal dimension of about 2.5.
 39. The device ofclaim 36, wherein each second nanostructure of the plurality of secondnanostructures defines a horizontal dimension that is about one third ofa horizontal dimension corresponding to each microstructure of theplurality of microstructures.
 40. The device of claim 36, wherein eachfirst nanostructure of the plurality of first nanostructures defines ahorizontal dimension that is about one half of a horizontal dimensioncorresponding to each second nanostructure of the plurality of secondnanostructures.